20.04.07 New-born Screening Flashcards

1
Q

Which committee is responsible for screening policies and programs in UK

A

UK National screening Committee

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2
Q

How many newborns are screened every year

A

800,000

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3
Q

What criteria did WHO develop to determine what disorders are suitable for screening

A
  • Clinically and biochemically well-defined disorder
  • Known incidence in populations relevant to the UK
  • Disorder associated with significant morbidity or mortality
  • Effective treatment available
  • Period before onset where intervention improves outcome
  • Ethical, safe, simple, robust screening test
  • Cost effective
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4
Q

What diseases are covered by UK newborn screening programme

A
  1. Pheylketonuria (PKU)
  2. Congenital hypothyroidism (CHT)
  3. Sickle cell anaemia
  4. CF
  5. Medium chain acyl-CoA dehydrogenase deficiency (MCADD)
  6. Maple syrup disease (MSUD)
  7. Homocystinuria (pyridoxine unresponsive) (HCU)
  8. Glutaric Acidaemia type 1 (GA1)
  9. Isovaleric Acidaemia (IVA)
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5
Q

Review of phenylketonuria (PKU)

A
  • AR
  • 1 in 10,000 in UK
  • Mutations in PAH gene, phenylalanine hydroxylase enzyme
  • Enzyme needed to metabolise phenylalanine (phe) to tyrosine (Tyr)
  • Defects in enzyme cause toxic amounts of phenylalanine to build up
  • If left untreated babies develop serious and irreversible mental disability
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6
Q

How is phenylketonuria screened

A
  • Tandem mass spectrometry is used to distinguish between PKU and other disorders
  • No genetic testing involved. Avoids the detection of carriers. Treatments available make prenatal testing an ethical dilemma.
  • Genetic testing can be useful as some mutations are amenable to treatment with BH4 supplements, reducing the need for strict dietary control.
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7
Q

Review of congenital hypothyroidism (CHT)

A
  • 1 in 3,000 babies born in UK
  • Inborn error of metabolism where thyroid glands fail to produce thyroxine.
  • Babies don’t grow properly, develop serious, permanent, physical and mental disability
  • 10% cases are genetic
  • Genetically heterogenous. Mainly AR, some ad
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8
Q

How is congenital hypothyroidism screened

A
  • Levels of thyroid stimulating hormone (TSH), also known as thyrotropin
  • Treated with thyroxine tablets, allowing normal development
  • Not all secondary hypothyroidism will be detected. Although they often have other health problems (jaundice, low blood sugar, small genitals), so often diagnosed easily
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9
Q

Review of medium-chain acyl CoA dehydrogenase (MCADD)

A
  • Affects 1 in 10,000 babies born in UK
  • 1 in 52-83 carrier frequency. Likely a Northern European founder effect. Rare in other ethnicities.
  • AR. Mutations in ACADM gene.
  • Leads to a buildup of medium chain fatty acids, in particular octanoylcarnitine (C8)
  • Body cannot efficiently use fats as part of glucose homeostasis. A problem in early infancy when glyconeolysis is not sufficient in periods of starvation.
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10
Q

What is screened in medium-chain acyl CoA dehydrogenase

A
  • Tandem mass spectrometry to measure C8 levels.
  • Mutation screening for c.985A>G p.(Lys304Glu), present in 88% cases
  • Functional MCAD protein contains 4 monomers that form a tetramer. Missense mutations cause tetramer to dissociate, reducing activity and affinity for substrates.
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11
Q

Review sickle cell disease

A
  • Affects 1 in 1,900 babies born in UK
  • AR
  • Red blood cells are sickle shaped, reducing flexibility. Unable to pass through narrow capillaries leading to vessel occlusion and ischaemia. Can lead to organ damage, stroke, infection, pain and death.
  • Haemoglobin A makes up 95% of haemoglobin. Has 2 alpha and 2 beta chains.
  • SCD caused by mutation in beta globin chain, HBB c.20A>T p.(Glu6Val).
  • More common in people originating from tropical regions where malaria is common. A single sickle cell gene confers an advantage.
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12
Q

Testing for sickle cell disease

A
  • High performance liquid chromatography (HPLC), isoelectric focusing (IEF), capillary electrophoresis.
  • HPLC: measures elution time of various haemoglobin proteins in various buffer solutions. Can detect carriers and affecteds
  • IEF: separates proteins by charge and molecular weight (gel with pH gradient).
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13
Q

Review of CF

A
  • Affects 1 in 2,500 babies
  • Carrier rate is 1 in 25 in UK
  • AR
  • Disorder when digestive system and lungs get clogged with thick sticky mucus. Poor weight gain and frequent chest infections.
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14
Q

Testing for CF

A
  • Looks for raised levels of immunoreactive trypsinogen (IRT)
  • Fluoroimmunometric assay. 2 monoclonal antibodies (1 bound to plate and one europium labelled) are directed against 2 antigens on IRT.
  • Genetics: common 4 mutation screen. F508del, Gly551Asp, Gly542X, c.489+1G>T
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15
Q

CF result interpretation

A
  • 2 mutations CF suspected. Immediate referral to CF specialist
  • 1 CFTR mutation, IRT on second blood spot. If elevated then CF suspected, if low then probably CF carrier
  • No mutation detected. If first IRT was above 99.99th centile then second blood spot taken at 21 days. If below 99.99th centile then CF not suspected.
  • Poor predictive value of IRT alone, so genetic testing needed.
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16
Q

Review of maple syrup disease

A
  • Incidence= 1 in 200,000 live births. Higher in certain ethnic groups
  • AR due to mutations in branched chain 2-keto acid dehydrogenase (BCKAD) complex.
  • Defects lead to accumulation of amino acids leucine, isoleucine, allo-leucine and valine. Cause toxicity in brain and skeletal muscle.
  • Genetic heterogeneity due to mutations in genes encoding subunits of BCKAD (BCKDHA, BCKDHB, DBT, DLD)
  • Vomiting, lethargy, progressive neurological deterioration, maple syrup odour to urine
17
Q

Screening of Maple syrup disease

A
  • Tandem mass spectrometry (ms/ms)
  • Quantifies the levels of leucine, isoleucine, allo-isoleucine and valine. Although cannot distinguish between them as they all have the same mass. Combined peak for all 4 analytes.
  • Elevated levels of “leucines”. Then followed up with measurement of allo-isoleucine in blood spots.
18
Q

Review of homocystinuria

A
  • Incidence is 1 in 100,000 live births. Higher in certain ethnic groups
  • AR due to mutations in CBS gene. Cystathionine beta-synthase.
  • Defects lead to catabolism of methionine, leading to toxic accumulation of homocysteine.
  • Learning difficulties, skeletal abnormalities, myopia, thrombotic episodes.
  • Treatment is low methionine diet. 50% are responsive to vitamin B6 (pyridoxine)
19
Q

Homocystinuria screening

A

-Tandem mass spectrometry (MS/MS) to measure levels of methionine (raised) and total homocysteine in blood spots.

20
Q

Review of glutaric acidaemia type 1 (GA1)

A
  • Incidence is 1 in 100,000 live births in Europe.
  • AR, due to mutations in glutaryl-CoA-dehydrogenase (GCDH) gene
  • Defective catabolism of glutaryl-A, an intermediate in break down of amino acids lysine, hydroxylysine and tryptophan. Leads to a toxic accumulation of glutaric acid.
  • Macrocephaly, encephalopathic crisis, GI infection or pneumonia.
  • R402W most prevalent mutation in Caucasians
  • Treatment is low protein, lysine-restricted diet. Supplementation of carnitine. Rapid treatment of ilness to prevent crises.
21
Q

Glutaric acidaemia type 1 testing

A
  • Tandem Mass spectrometry (MS/MS)
  • Quantifies glutarylcarnitine (C5DC) in blood spots
  • Won’t detect GA1 low excretors
22
Q

Review of isovaleric acidaemia (IVA)

A
  • Incidence 1 in 100,000
  • AR, mutations in IVD gene.
  • Deficiency in mitochondrial enzyme isovaleryl-CoA-dehydrogenase
  • Defective catabolism of the amino acid leucine, with toxic accumulation of isovaleric acid and its glycine and carnitine derivatives.
  • Metabolic crisis, vomiting, lethargy, progressing to coma, failure to thrive, dev delay.
  • Treatment: low protein diet. Glycine and L-carnitine can be administered to help clear excess isovaleric acid from body.
23
Q

Isovaleri acidaemia testing

A
  • MS/MS. Detects elevated C5 (isovalerylcarnitine) in blood spots
  • Urine organic acid analysis (differentiate between IVA and GA2)